Vaginal Tumors in the Pediatric Age Group: The Children's Cancer Hospital Egypt (CCHE)-57357 Experience

Background: Primary vaginal malignancies are rare in children. Their management has evolved during the last decades from radical surgery to neoadjuvant chemotherapy followed by local control with conservative surgery or radiotherapy. Aim: To describe the presentation, management, and outcome of pediatric vaginal malignancies. Methods: Retrospective review of the medical records of children with 1 ry vaginal malignancies who had been treated at the Children’s Cancer Hospital Egypt (CCHE)-57357 from June 2007 till December 2018. Results: During the 11 years, 34 pediatric patients with 1 ry vaginal malignancies were identified. The histopathology was rhabdomyosarcoma (RMS) in 19 (55.9%) patients, germ cell tumor (GCT) in 13 (38.2%), and clear cell adenocarcinoma (CCA) in two (5.9%). Vaginal bleeding was the presenting symptom in 65% of the patients. The 5-year overall survival and event-free survival rates were 73.7% and 77.8%, respectively, in RMS patients. In GCT patients, the 5-year overall survival and event-free survival rates were 84.6% and 61.5%, respectively. One of the two CCA patients died because of disease progression and the other was alive with progressive disease. Conclusions: Primary vaginal tumors are rare in children and generally have a good prognosis. Treatment with chemotherapy only or with either conservative surgery or radiotherapy may achieve an excellent outcome in pediatric primary vaginal RMS and GCT.


Introduction
Genital tract tumors are rare in children 1

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The management of pediatric vaginal tumors has changed from radical surgery in the 1970s and early 1980s to upfront chemotherapy followed by local control with surgery or radiotherapy 2 .
The differentiation between RMS, YST, and CCA by cytological examination is often difficult, that is why histopathology and immunohistochemistry are needed 1,3 . Rhabdomyosarcomas express myogenin and myoD1 which are highly sensitive and specific 4 . The clear cells of YST are of different patterns with Schiller-Duval bodies and hyaline globules, which are PAS-positive, diastase-resistant, alphafetoprotein (AFP) positive, and LeuM1 negative. On the other hand, the hyaline globules in CCA are PASpositive, diastase-sensitive (glycogen), AFP negative, and LeuM1 positive 5 .
Rhabdomyosarcoma of the female genital tract, including the vagina, uterus, and cervix, comprises 4% of RMS cases 1 . The tumors also rarely occur in the cervix or uterine fundus and often are described in another term as a "cluster of grapes" 6 . Vaginal RMS in infants is usually described as sarcoma botryoides 7 . Vaginal RMS is considered a favorable site with a 5-year overall survival (OS) rate greater than 90% 1, 2 but, because of its specific location, it poses unique challenges for local tumor control 8 .
Malignant germ-cell tumors (GCTs) are rare tumors of childhood, accounting for less than 3% of pediatric malignancies. Endodermal sinus tumor (EST) is the most common histologic subtype of malignant GCTs. The vagina is a rare site for GCTs 7 . Partial vaginectomy with combination chemotherapy is the most recommended line of treatment. The surgery eradicates local tumor cells and makes subsequent chemotherapy more effective, and simple tumor excision is not sufficient. Serum AFP level is a valuable marker for diagnosis and monitoring the recurrence of vaginal EST in infants 7 .
Mesonephric adenocarcinoma of the cervix and vagina is very rare in childhood, with a median age at presentation of 15 years. Patients usually present with vaginal bleeding. Adenocarcinoma of the cervix or vagina in adults usually presents with stage I / II disease. There is a high incidence (24%) of advanced disease (stage III / IV) in children and adolescents 9 . The treatment of choice for vaginal adenocarcinoma is surgical resection 8 . This is followed by radiation therapy for residual microscopic disease or lymph node spread. The role of chemotherapy in the management of CCA is debatable and drugs such as carboplatin and paclitaxel, have been used 2 .
In this study, we describe the clinical presentation, treatment modality, and outcome of vaginal tumors in pediatric patients treated at the Children's Cancer Hospital Egypt (CCHE)-57357.

Methods
A retrospective review of the electronic medical records of children with vaginal tumors treated at the CCHE-57357 over 11 years from June 2007 to June 2018. Patients were followed up until March 2019.
The data retrieved included: age at diagnosis, presenting symptoms, histological findings, stage and risk stratification, systemic chemotherapy given, local control intervention, and outcome.
The initial workup at the presentation included a computerized tomography scan or magnetic resonance imaging and vaginoscopy to assess local disease (tumor size and invasiveness). Computerized tomography scans of the chest and bone scans were done for evaluation of metastatic disease. Bone marrow aspirate and biopsy were performed for cases of vaginal RMS and tumor markers (AFP and beta-human chorionic gonadotropin [BHCG]) were measured in GCT cases. Alpha-fetoprotein half-life (AFP T1/2) was calculated and defined as the time required for the AFP amount in the body to be reduced by one-half. Rhabdomyosarcoma was staged according to the TNM system of the International Union against Cancer (UICC) and the Intergroup Rhabdomyosarcoma Study Group (IRSG) clinical grouping system 10 . Vaginal GCT cases were stratified according to the Children Oncology Group (COG) staging and risk stratification system for extragonadal GCT (8 th edition of AJCC/UICC, 2016).
A biopsy was taken for pathological diagnosis. Rhabdomyosarcoma usually embryonal or botryoid subtype (sarcoma botryoides) is positive to desmin with or without myogenin. Yolk sac tumors (or endodermal sinus tumors), which may form histologic patterns that resemble embryonal       She then received external beam radiotherapy (total dose = 60 Gy) to the primary tumor and involved lymph nodes with concomitant cisplatin as a radiosensitizer. One year later, she presented with local disease progression and pulmonary metastasis and was under supportive/palliative care at the last assessment.

Discussion
Primary vaginal tumors are very rare in the pediatric age group. Over 39 years, only 18 patients <21 years of age out of 4485 (0.4%) treated at St. Jude Children's Research Hospital had primary vaginal tumors 1 . In the current study, RMS was the commonest pathology followed by GCTs which agrees with the study from St Jude Children's Research Hospital in which 13/18 (72%) of reviewed primary pediatric vaginal neoplasms were RMS 1 . On the contrary, another study reported that endodermal sinus tumor is more common (17/24, 71%) 13 . The embryonal variant is the most common subtype of RMS (60-70%) 14 , which agrees with the findings of this study where 74% of RMS were embryonal.
Rhabdomyosarcoma is a mesenchymal malignant neoplasm originating from the embryonic myotome. It is the most prevalent soft tissue tumor in children. Primary vaginal RMS and YST in childhood are rare and they are diagnosed mostly in children younger than six years of age 15 . In our study, 12 cases out of 19 (63%) were between 1-10 years. In young and adolescent patients, the cervix and uterus are more prevalent, whereas, in infants, vaginal lesions are common 14 . The survival of adolescent and adult patients with RMS is significantly lower than that of children. Although trials are ongoing to improve its outcome, standard treatment protocols are still lacking. In the past, treatment protocols for primary vaginal EST and RMS were very aggressive and led to serious sequelae such as loss of the reproductive function due to radical surgery (ranging from vaginectomy to total pelvic exenteration) or external radiation and vaginal brachytherapy 13 . The development of chemotherapy allowed a conservative strategy to maintain sexual and reproductive function for the future in this group of patients 13 . Protocols are currently trying to reduce the intensity of treatment and alleviate treatment-related complications, especially in patients in the low-risk group 15 .
Management of vaginal tumors has progressed from radical surgery to neoadjuvant chemotherapy followed by surgery or radiotherapy.
Radical surgical resection was reserved for truly persistent or recurrent disease 16 . Local control by radiotherapy is associated with significant late effects 17 . In our study, most RMS cases had radiotherapy as a measure of local control (16 out of the 19 patients). In the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group (MMT) studies patients who achieved complete remission with primary chemotherapy did not receive local treatment 8. Management may also include radical surgery with or without external-beam radiotherapy. Another conservative approach was also adopted to do a limited surgical intervention and, when feasible, with intracavitary brachytherapy 8 . The conservative approach resulted in a local failure of around 18% and a 5-year OS of 91%. The European pediatric Soft tissue sarcoma Study Group (EpSSG) protocol and COG initially adopted the conservative approach early in 1997. But COG reported local recurrence in patients with partially resected vaginal RMS as they used a response-related approach that could delay or eliminate radiotherapy 8 .
Chemotherapy in RMS is used to decrease tumor size and eliminate micrometastases. VAC (vincristine, actinomycin-d, and cyclophosphamide) and IVA (ifosfamide, vincristine, and doxorubicin) were the chemotherapy regimens mostly used in the COG and European studies, respectively. In our study, cases were treated according to COG protocols and received chemotherapy in the form of VAC. Sixteen cases out of 19 in our study had radiotherapy as a method of local control and initial partial resection was done in only one case. As a salvage treatment, radical total hysterectomy was done in a recurrent RMS case and another one mesonephric adenocarcinoma. The current findings confirm that of Fernandez-Pineda et al, who reported that RMS arising in the vagina has an excellent prognosis and the importance of a local therapy that leads to a high rate of cure 1 . In the present study, 15 out of 19 RMS patients are alive in CR.
GCT represents around 3% of all malignancies in children and extragonadal GCT, especially in the vagina is rare and usually presents by vaginal bleeding in girls below 3 years. In our cases, the age ranged from 8 months to 2.8 years and vaginal bleeding was the main presentation. Yolk sac tumor was the most common GCT pathology in our study (9/13 GCT patients). Alpha-fetoprotein is considered an important marker for the diagnosis and assessment of treatment response of GCTs 18 . In our group of patients, all GCT cases presented with elevated AFP with a half-life (T1/2) ˂10 days which indicates a good response to chemotherapy, with normalization of markers post 2 nd cycle of chemotherapy in all cases except in one. The progressive rise of AFP after normalization is an indicator of relapse or progression.
Upfront surgery followed by VAC chemotherapy was the usual management in the past, and only a few cases with small tumors had surgery with organ preservation 19, 20 . Regimens including platinum drugs have a superior response rate and higher survival in pediatric GCT in general, with the current 2-year survival for vaginal GCT reaching 70% 21 . A biopsy followed by chemotherapy and vaginal preservation in patients showing a complete tumor response including AFP normalization is the current approach for vaginal malignant GCT 1 . This approach is what we followed in our patients as 9/13 of them underwent excisional biopsy by colposcopy after 4 PEB cycles. Only one patient underwent a total hysterectomy. Radical surgery for vaginal YST is unwarranted but may be required for tumors infiltrating into surrounding structures 3 . Others recommended partial vaginectomy / local tumor excision for better tumor eradication and lower risk of local recurrence 22 .
Vaginal CCA usually occurs in adolescence and has been very rarely reported under the age of 6 years 23 . Both cases in the current study were above ten years old at presentation. The aggressive pattern is often seen in young children with higher survival rates for patients who undergo tumor resection with pelvic and para-aortic nodal dissections, even in patients with early-stage disease. Post-operative radiotherapy is reserved for microscopic residual or nodal metastasis 23 .
The current study is limited by the small number of patients and being from a single institution. Prospective multi-institutional studies are needed to optimize the management of these rare tumors.